Binding to serum α₁‐acid glycoprotein and effect of β‐adrenoceptor antagonists in rats with inflammation

Abstract

1 The P-blocking effect of 4 P-adrenoceptor antagonists with different pharmacokinetic properties was studied after intravenous and intraportal administration to control rats and to rats with experimental inflammation. 2 In rats with inflammation the effects of propranolol and oxprenolol, which are mainly bound to a,-acid glycoprotein (ax-AGP), were significantly less after intravenous administration, but not after intraportal administration. In contrast, for metoprolol and atenolol, which are only negligibly serum bound, no difference was observed between control rats and rats with inflammation for either route of administration. 3 Total and unbound serum concentrations of propranolol were measured 20 min after intravenous and intraportal administration. 4 After intravenous administration, in the rats with inflammation total concentrations of propranolol were more than twice, and unbound concentrations less than half those of control rats. After intraportal administration the total concentrations were 8 times, and the unbound concentrations 3 times higher in the rats with inflammation. 5There was a significant correlation between the P-blocking effect and the unbound concentrations of propranolol after intravenous administration, but not after intraportal administration. The latter finding is probably because the unbound concentrations were supramaximal.

Effect of α1‐Acid Glycoprotein on the Pharmacokinetics of Tamsulosin in Rats Treated with Turpentine Oil

“…As for propranolol, total plasma levels were elevated after intravenous dosing by the subcutaneous or intramuscular injection of turpentine oil, whereas the unbound levels were decreased. 20 In addition, t 1 /2 was shortened by the treatment. 18 These observations are similar to those in TAM.…”

“…On the contrary, the plasma Alb level was almost constant between them and less affected by the turpentine oil treatment The turpentine oil treatment is an easy method to elevate plasma ␣ 1 -AGP levels temporarily because it induces regional inflammation. [18][19][20] In addition, it has been reported that ␣ 1 -AGP can be induced by drugs such as phenobarbital. 21,22 Although many basic drugs are known to bind to ␣ 1 -AGP, TAM binding to human ␣ 1 -AGP is very high compared with many other drugs.…”

Alpha 1-Acid Glycoprotein (AAG) Levels in Healthy and Pregrant Beagle Dogs

“…The pharmacokinetics, efficacy and toxicology of basic drugs are influenced by the AAG variations in humans [2,6,11,12,[16][17][18][19]. Action is therefore required sometimes to change serum AAG levels before basic drugs are administered.…”

Disease–drug interaction: Reduced response to propranolol despite increased concentration in the rat with inflammation

“…[11][12][13] The effect of various inflammatory conditions on the pharmacokinetics of propranolol, a b-adrenergic antagonist, has been studied by many investigators who have all observed reduced clearance. [1][2][3][5][6][7][8][9] However, the therapeutic consequences of the observed increase have not been examined. It has been reported that for sotalol, another b-adrenergic antagonist, that inflammation causes reduced potency, which is attributed to receptor downregulation.…”

“…Several investigators have reported substantial increases in the plasma concentration of many drugs due to diminished clearance caused by inflammation. [1][2][3][4][5][6][7][8][9][10] This reduction in clearance is often attributed to a diminished hepatic metabolism brought about by increased expression of proinflammatory mediators such as nitric oxide (NO) and/or cytokines. [11][12][13] The effect of various inflammatory conditions on the pharmacokinetics of propranolol, a b-adrenergic antagonist, has been studied by many investigators who have all observed reduced clearance.…”